1. Field of the Invention
The invention is directed to a sustained- or controlled-release solid composition for the oral cavity or "pharmaceutical oral patch" that adheres to hard dental surfaces, such as teeth and dentures, and releases a pharmaceutical agent. Release of the agent is for a predetermined period of time and at a predetermined concentration. The site of action of the agent is topical, local or systemic. The invention is also directed to suitable polymers for the pharmaceutical oral patch, in particular the polymers known as Eudragit.TM.. The patch can comprise a single adherent release layer or a non-adherent layer adhered in the oral cavity by a separate adherent layer.
2. Related Art
The advantages of controlled-release products are well-known in the pharmaceutical field and include the ability to maintain a desired level of medicament over a desired period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same level.
Oral controlled-release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. The art describes free forms, such as sublingual tablets, troches, and buccals. In addition to non-attached oral sustained- or controlled-release forms, other forms are designed to adhere to the oral mucosa and deliver an active pharmaceutical agent either directly into the oral mucosa, or into the saliva. Ointments and other sticky adhering compositions also have been used. The active ingredient in all these forms can act locally or systemically.
U.S. Pat. No. 4,829,056 describes a buccal tablet consisting of etorphine, at least one monosaccharide, disaccharide or mixture thereof, and a mixture of xanthan gum and locust bean gum in a weight ratio of 3:1 to 1:1, wherein the total weight of the mono- and/or disaccharides relative to the combined weight of xanthan and locust bean gums is in the ratio of 20:1 to 3:1. The buccal tablet is intended to be placed between the gingival surface of the jaw and the buccal mucosa where it gels to produce a soft hydrated tablet which may be retained in position so as to provide release of etorphine for up to two hours. The buccal tablet is said to provide improved bioavailability.
U.S. Pat. No. 4,948,580 describes a bioadhesive composition which may be employed as an oral drug delivery system and includes a freeze-dried polymer mixture formed of the copolymer poly(methyl vinyl ether/maleic anhydride) and gelatin dispersed in an ointment base. This composition is said to be useful to deliver active ingredients such as steroids, antifungal agents, and antibacterial agents, to the oral mucosa.
U.S. Pat. No. 4,597,959 describes a cosmetic breath freshener composition in wafer form which is said to have slow release properties. The composition includes a multiplicity of microencapsulated liquid droplets of flavoring material contained in an adhesive base.
U.S. Pat. No. 5,077,051 describes bioadhesive microcapsules which comprise xanthan gum, locust bean gum, a bulking agent and an active agent. The microcapsules are said to be useful for delivering buffering agents to the oral cavity for anticarious purposes. The microcapsules are prepared by preparing a hot aqueous solution or suspension of the active agent; adding xanthan gum, locust bean gum and a bulking agent to form a viscous solution; and then (a) cooling and then drying the viscous solution to obtain a solid material which is then formed into microcapsules, or (b) spray-drying the viscous solution to form the microcapsules.
U.S. Pat. No. 4,915,948 describes a tablet which is said to have improved adhesion to mucous membranes. The tablet includes a water soluble biopolymer selected from xanthan gum, a pectin and mixtures thereof, and a solid polyol having a solubility at room temperature in water greater than about 20 g/100 g solution.
U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757, describe a controlled release excipient comprised of synergistic heterodisperse polysaccharides (e.g., a heteropolysaccharide, such as xanthan gum in combination with a polysaccharide gum capable of cross-linking with the heteropolysaccharide, such as locust bean gum) that is capable of processing into oral solid dosage forms using either direct compression, following addition of drug and lubricant powder, conventional wet granulation, or a combination of the two. Release of the medicament from the formulations is reported to proceed according to zero-order or first-order mechanisms.
U.S. Pat. No. 4,059,686 describes a pharmaceutical preparation for oral cavity administration characterized by being a mixture of a pharmacologically active agent, a pharmaceutical carrier, and sodium polyacrylate in conventional dosage form. It adheres strongly to a local site and dissolves gradually over a prolonged period of time, releasing appropriate amounts of the active agent. The preparation is designed to adhere to mucosal membranes.
U.S. Pat. No. 4,876,092 describes a sheet-shaped adhesive preparation comprising an adhesive layer containing, as essential components, a carboxyvinyl polymer, a water-insoluble methacrylic copolymer, a polyhydric alcohol, and a pharmaceutically active agent, and a water-impermeable and water-insoluble carrier layer containing, as essential components, a pharmaceutically active, water-insoluble, film-forming high molecular weight compound and a plasticizer, which can adhere within the oral cavity over a period of time and release an active agent. The preparation is designed to be adhered to the mucous membrane.
U.S. Pat. No. 3,972,995 describes a dosage form for buccal administration of a drug, and which is directly applicable to the interior surfaces of the mouth. The dosage form is comprised of a support member which is water-insoluble, waterproof and flexible, a moisture-activated adhesive precursor applied to one surface of the support member, and an active ingredient applied to the central portion of the support member, either directly or dispersed in a matrix. The dosage form is applied directly to the interior surface of the mouth. Contact with saliva activates the adhesive and causes the support member to adhere to the interior surface of the mouth, thereby exposing the active ingredient to a limited area of the oral mucosa while isolating the active ingredient from the remainder of the oral environment.
U.S. Pat. No. 5,330,761 describes a controlled release bioadhesive tablet which includes a locally active agent, a heterodisperse gum matrix, and a pharmaceutically acceptable diluent. The final product adheres to mucous membranes and releases the locally active agent over a desired period of time.
Nagai, T. et al. (J. Cont. Rel. 6:353 (1987)) describes a sustained-release tablet capable of sticking tightly to human gingiva and not the cheek mucosa. Further described is a self-administered plaster with a water-impermeable backing layer (film).
U.S. Pat. No. 4,772,470 discloses an oral bandage comprising a soft adhesive film comprising a mixture of polycarboxylic acid and/or a polycarboxylic acid anhydride and a vinyl acetate polymer in a compatible state, and an oral preparation comprising such an oral bandage having incorporated therein a topical drug. The oral bandage or preparation is reported to exhibit strong adhesion of long duration when applied to the oral mucosa or teeth. This patent purports to teach a composition for topical administration of pharmaceutically active agents. It is drawn primarily to the use of anesthetic compositions, but may comprise other agents as well. The composition comprises the active agent in a pharmaceutically acceptable solvent, and in an admixture also includes a bioadhesive. This patent, however, does not teach the use of a sustained-release composition wherein the composition can be attached to a tooth or other dental surface by separate adhesive.
U.S. Pat. No. 4,900,554 describes an adhesive device for application to body tissue having an adhesive layer and a backing layer positioned over one side of the adhesive layer. The adhesive layer includes one or more acrylic acid polymers having adhesive properties upon dissolution or swelling in water and at least one water-insoluble cellulose derivative. The backing layer is water-insoluble or sparingly water-soluble. This patent discloses a composition comprising the active agent in an admixture that also includes a bioadhesive. Further, it includes a backing layer so that the adhesive does not adhere to adjacent areas. Further, the patent does not teach the use of a sustained-release composition which can be attached to a tooth or other dental surface by a separate adhesive.
U.S. Pat. No. 5,446,070 relates to compositions and methods for topical administration of pharmaceutically active compounds and specifically to anesthetic compounds for topical administration. The invention is a flexible bioadhesive composition for topical application comprising a pharmaceutically active agent, a solvent and a plasticizer, in admixture with a polysaccharide bioadhesive carrier, wherein the composition is substantially free of water, substantially water-insoluble, and wherein the pharmaceutically active agent is present in a non-crystallized form. The patent discloses that an exceptionally high loading of anesthetic agents can be added to a carrier without loss of the adhesive properties, so that more rapid delivery of an anesthetic agent to a tissue without substantial crystallization of the agent can occur. The reference discloses the use of the composition for topical administration to hard tissue such as teeth. However, the active agent is an admixture with the adhesive agent. The patent does not disclose a drug delivery device attached by means of an adhesive agent.
European Patent Application 223 245 discloses a curable composition containing methacrylate monomers and a polymerization initiator for application to teeth and having the property of in situ polymerization to form a hardened filler. The reference discloses the use of such filler in combination with an active agent, thereby releasing the active agent from the hardened filler. These compositions are not used, however, to form a sustained release device attached by means of an adhesive composition.
Furthermore, each of the above-cited references further discuss sustained-release compositions, many of which can be used to release a pharmaceutically active agent in the oral cavity.
Several problems are associated with controlled-release or sustained-release formulations in the oral cavity.
A major problem is providing prolonged release at effective concentrations. For example, fungal infections beginning in the mouth and then entering other parts of the body are life-threatening to immuno-compromised patients. It is thus desirable to release antifungal agents on an ongoing basis. However, it is very difficult to achieve.
Buccal tablets and sublingual tablets are pharmaceutical preparations primarily intended for systemic effect. These tablets are placed between the cheek and gingival or under the tongue and allowed to dissolve slowly. The drugs absorbed through the oral mucous membrane enter directly, not through the portal circulation but through the systemic circulation. An advantage of these tablets is in the efficient absorption of the drug, because the drug is not decomposed by the liver. However, if the disintegration and dissolution of the tablet are too rapid, the object of this method of administration is not achieved.
A problem with these sustained-release devices involves the area of comfort. Patients often reject these oral sustained-release devices because they have a "foreign" feeling. As a result, these devices are often dislodged by the patient.
Recently, a tablet for stomatitis has been developed which is applicable directly to the affected region. But this preparation is also hard and has a certain thickness, and persons using it are aware of its presence. Accordingly, the tablet may be dislodged with the tongue and swallowed during eating and drinking. Therefore, it is difficult to retain within the oral cavity for a long time.
Moreover, the known preparations are usually composed of components which are soluble or disintegrable within the mouth. Thus, the pharmaceutically active agents contained in the preparations are mostly swallowed without being absorbed through the mucous membrane in the oral cavity. Thus, these preparations are not completely satisfactory as a sustained- or controlled-release preparation for the oral cavity.
In order to retard disintegration of the above said preparations, the following trials have been made without successful results as a preparation for oral cavity administration:
1. to add larger amounts of a binder, without employing a disintegrant, such as starch; PA1 2. to add a large amount of hydrophobic lubricant, such as magnesium stearate; PA1 3. to coat the tablet with a water-repellent substance such as wax or paraffin.
Ointments are not satisfactory for oral cavity administration because of insufficient adhesion and rather high solubility.
Mucosal patches, which demonstrate good adhesion for extended periods of time, cause adverse reactions like mucosal itching and irritation at the patch sites or even necrosis in severe cases. (Contact-Dermatitis 25(4):230-6 (1991); Maturitas 13(2):15-4 (1991).) In addition to health complications, the side effects profile of a product can lead to added therapeutic costs by requiring treatment by physicians or visits to emergency rooms.
Another problem is localized release to teeth. That is, the application of agents that are designed to be delivered to teeth, for example, tooth whiteners and desensitizing agents, are for the most part wasted because delivery is to the whole oral cavity and not local to the tooth.
Another problem is the difficulty of application of sustained release devices for the oral cavity.
Controlled Release Drug Formulations Containing Eudragit.TM.
Eudragit.TM. polymers form a diverse family of polymers whose common feature is a polyacrylic or polymethacrylic backbone that is compatible with the gastrointestinal tract and which have been widely used in pharmaceutical preparations, especially as coatings for tablets. Eudragit.TM. polymers have been used, among other things, for controlled release of pharmaceutical agents. In most formulations, Eudragit.TM. is used for coating a core containing the pharmaceutical agent.
Ndesendo et al., J. Microencap. 13:1-8 (1996) disclosed coacervation of a highly water soluble drug using Eudragit RS-100.TM. as the coating material.
Benkataram et al., J. Microencap. 13:519-25 (1996) disclosed a sustained release formulation in which an iron chelator is microencapsulated in either Eudragit RS.TM., RL.TM., or L-90.TM..
Narisawa et al., J. Pharm. Sci. 85:184-8(1996) disclosed drug-containing beads coated with Eudragit NE-30D.TM..
Friend, D. R., J. Microencap. 9:469-80 (1992) disclosed sustained release formulations of a core drug coated with either Eudragit L-100.TM., S-100.TM. or E-100.TM..
Prantera et al., Gastroenterology 103:363-8 (1992) disclosed a delayed release formulation of ASA coated with Eudragit S.TM..
Morishita et al., Drug Des. Deliv. 7:309-19 (1991) disclosed the preparation of erythromycin microspheres using Eudragit L-100.TM. as the coating material to produce controlled release of the drug.
Tirosh et al., J. Contr. Rel. 45:57-64 (1997) disclosed the incorporation of Eudragit RL-100.TM. into polycarbophil to compensate for the poor mechanical properties of polycarbophil in the preparation of solid dosage forms for oral delivery of drugs.
Lee et al., Int. J. Pharmaceut. 144:37-46 (1996) disclosed drug containing alginate beads coated with Eudragit RS-100.TM. and aluminum tristearate (as a plasticizer) to create sustained-release dosage forms for melatonin.
Govender, J. Microencap. 14:1-13 (1997) disclosed microencapsulated Eudragit RS-30D.TM.-coated controlled release pellets.
Morishita et al., Int. J Pharm. 78:1-8 (1992) disclosed Eudragit L-100.TM. microspheres as an oral dosage form for the release of insulin.
Kaura et al., Drug Dev. Ind. Pharm. 7:925-938 (1988) disclosed an oral dosage formulation containing a coating of Eudragit E-100R.TM..
WO/97/02020 discloses oral pharmaceutical compositions for slow release of an anti-microbial agent in which the release-controlling layer can be Eudragit RS.TM., RL.TM. or RTM.TM. and is also coated by Eudragit L.TM. or Eudragit RTM.TM..
WO/91/19486 discloses microspheres with a core containing drug and two or more enteric coatings, wherein the enteric coatings can be Eudragit L-100-55.TM. (RTM) or Eudragit E-100.TM. (RTM).
U.S. Pat. No. 5,096,717 discloses controlled release oral dosage forms containing a coating of Eudragit L-30D.TM..
Japanese Application No. 61093133 (now JP 92038726) describes a buccal tablet comprising a pharmaceutical-containing solid sandwiched between an adhesive film and a film not soluble in water, for example, Eudragit RTM.TM.. The tablet is described as being highly adhesive to the oral cavity for long slow release of the pharmaceutical ingredient from the solid into the oral cavity. The Eudragit.TM. layer and the drug layer are discreet layers. There is no liquid dispersion or solid dispersion.
Alvarez-Fuentes et al., Drug Dev. Ind. Pharm. 20:2409 (1994) discloses co-precipitation of morphine and Eudragit L-30.TM. as a carrier. Chemical association between the morphine and the Eudragit L-30.TM. carrier is by hydrogen bonding. The polymer is neutralized using NaOH, KOH, etc.
None of the above references discloses a liquid composition containing a Eudragit.TM. polymer dispersed with a pharmaceutical agent, which liquid dispersion is then capable of dying to form a solid product in which the pharmaceutical agent is dispersed in the Eudragit.TM. polymer matrix.
However, liquid dispersions of Eudragit.TM. with a pharmaceutical agent, which dispersions can be dried to form a dispersion of the pharmaceutical agent in the Eudragit.TM. polymer have been described.
Kim et al., J. Pharm. Sci. 81:537-40 (1992) described a hydrogel and xerogel preparation containing a medicinal component dispersed in a gel matrix of Eudragit S.TM., Eudragit L.TM., or Eudispert.TM.. The gel is bioadhesive in the rectum. The matrix is bioerodible. Properties of the matrix are altered with NaOH, KOH, and the like.
Vyas et al., J. Microencap. 8:447-54 (1991) described dispersions of diastase in Eudragit RS-100.TM..
Devay et al., Acta. Pharm. Hung. 58:166-72 (1988) described antihistamine dispersions into aqueous Eudragit.TM..
None of these formulations, however, has been used to achieve controlled release of a pharmaceutical agent in the oral cavity.
U.S. Pat. Nos. 5,160,737 and 5,330,746 disclose a sustained release liquid polymer composition comprising Eudragit L.TM., S.TM., RL.TM., or SL.TM. and a pharmaceutical agent. U.S. Pat. Nos. 5,160,737 and 5,330,746 use the formulation for preventing dental caries, periodontal disease, and tooth hypersensitivity by brushing or spraying the formulation onto the teeth and gingivae forming a film. Thus, the solid formulation provides controlled-release of a drug into the oral cavity. However, there is no disclosure or suggestion of forming a delivery vehicle other than the film.
Accordingly, there is a need for an oral controlled-release pharmaceutical delivery device with the following characteristics. Release can be sustained at desired concentrations for an extended desired period of time. Necrosis is avoided. Release can be localized to teeth. Application is easy and uncomplicated. Patient comfort is provided in that the device is comfortable and does not impart a "foreign" feeling to the oral cavity. Buccal absorption is facilitated, resulting in rapid systemic delivery of the released agent. Localized treatment of the oral mucosa is provided. The device is easily removable, in that it is not bonded to the attachment site (i.e., teeth) physically or chemically. Therefore, no scraping or chemical treatment is required to remove the device, although the device is available for release, holding to the site for an extended period of time (i.e., several hours).